Nicotine is the world's most widely used addictive substance. Nicotine abuse, in the form of smoking, causes many chronic diseases and almost 20% of the deaths in developed countries. The mechanisms of nicotine's addictiveness are well studied. However nicotine has behavioral effects distinct from its physically addictive qualities, and these contribute to its popularity. Nicotine is said to elevate mood and arousal, reduce pain, and improve attention, working memory, and the rapid processing of sensory information. The mechanisms for these effects of nicotine are very poorly understood. Nicotine receptor in the brain have recently been implicated in a familial form of epilepsy and other neurological and psychiatric disorders, and drugs with nicotinic activity may have potential in the treatment of Alzheimer's and Parkinson's disease. The goal of this proposal is to study the cellular mechanisms of nicotine's effects on the forebrain, in particular the sensory neocortex. Neocortex and its connections comprise 80% of human brain volume, and it is essential for normal sensation, movement, memory and cognition. Nicotine's direct action on neocortex probably plays a major role in the drug's diverse effects on behavior. Nicotine binds to neuronal nicotinic acetylcholine receptors : in neocortex neuronal nicotinic acetylcholine receptors are abundant on the input (I.e. Thalamocortical) synapses to the cortex, and on some inhibitory and pyramidal neurons. The aims of this investigation are to test the hypothesis that nicotine, and the activation of specific neuronal nicotinic acetylcholine receptors, alters the strength and dynamics of input synapsis to the neocortex, modulates synaptic inhibition and inhibitory neurons, and thus systematically changes the way the neocortex transforms sensory information from the thalamus. Experiments will be performed in vitro and in vivo in the somatosensory system of rats. A formal computational model will be used to understand how nicotine's effects on neurons and synapses lead to complex but predictable alterations of the neocortical network, and thus alter sensation.